103 Long non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity

Abstract

Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and its incidence is increasing globally. Long non-coding RNAs (lncRNAs) are involved in various biological processes and their role in cancer progression is emerging. We have studied the role of lncRNAs in the progression of cSCC. Whole transcriptome analysis of cSCC cell lines (n=8) and normal human epidermal keratinocytes (n=4) revealed marked upregulation of a specific long intergenic ncRNA, LINC00162, in cSCC cells. Expression of LINC00162 in tissue sections representing different stages of epidermal carcinogenesis, i.e. normal skin (n=9), actinic keratosis (AK) (n=26), cSCCs in situ (cSCCIS) (n=20), and invasive cSCCs (n=21) was analyzed by RNA in situ hybridization. Expression of LINC00162 was detected in tumor cells in cSCC, cSCCIS and AK, whereas no signal was detected in normal skin. Analysis of the LINC00162 positive tissue sections revealed that the number of positive sections increased with the progression from AK (23%) to cSCCIS (35%) and cSCC (43%). The expression of LINC00162 in cSCC cells was upregulated by inhibition of p38α and p38δ MAPKs. Knockdown of LINC00162 inhibited proliferation and migration of cSCC cells and suppressed growth of human cSCC xenografts in vivo. Knockdown of LINC00162 inhibited ERK1/2 activity and upregulated expression of dual specificity phosphatase DUSP6 in cSCC cells. Based on these observations, LINC00162 was named PICSAR (P38 Inhibited Cutaneous Squamous cell carcinoma Associated lincRNA). These results provide mechanistic evidence for the role of PICSAR in promoting cSCC progression via activation of ERK1/2 signaling pathway by downregulating DUSP6 expression. These results also identify PICSAR as a novel biomarker and putative therapeutic target in unresectable and metastatic cSCC.